1. Field of the Invention
The present invention relates to a process for the preparation of bioabsorbable polyester for use in medical devices such as surgical sutures, matrices for sustained release of drugs and internal splint-plates in fracture fixation. More particularly the invention relates to a process for preparing bioabsorbable polyesters, that is, a glycolic-acid based polymer, lactic-acid based polymer and glycolic-acid/lactic-acid based copolymer, which contain almost no residues of unreacted monomers or volatile ingredients of low molecular weight.
2. Prior Art of the Invention
Bioabsorbable polyesters having recurring structural units represented by the formula (I) : ##STR1## wherein R.sub.1 and R.sub.2 are a hydrogen atom or a methyl group and can be the same or different, are divided into a glycolic-acid based polymer wherein a 80 to 100% portion of R.sub.1 and R.sub.2 is a hydrogen atom and a 0 to 20% portion is a methyl group, and a lactic-acid based polymer wherein a 0 to 80% portion of R.sub.1 and R.sub.2 is a hydrogen atom and 20 to 100% portion is a methyl group.
The former glycolic-acid based polymer has hydrolyzability and bioabsorbability. High molecular weight polymers of glycolic acid may be processed into fibers and used for materials of sterile surgical treatment such as sutures and gauze. Surgical sutures of glycolic-acid based polymer have already been marketed from ACC Co. under the trade mark of Dexon (100% by mole of glycolic acid structure) and from Ethicon Co. under the trade mark of Vicril (from 85 to 90% by mole of glycolic acid structure and from 10 to 15% by mole of lactic acid structure).
The lactic-acid based polymer is an interesting bioabsorbable material which is nonenzymatically decomposed in vivo into glycolic acid and lactic acid. These acids are finally converted to carbon dioxide and water through a metabolic pathway and are excreted from the organism.
Lactic-acid/glycolic-acid copolymer and lactic acid homopolymer are particularly excellent in processability and solubility in various solvents. These polymers are hence processed into pellets, needles, films and microspheres, and employed for the matrix for sustained release of drugs for use in internal imbedding and intravenous injection. High molecular weight homopolymers of lactic acid may be particularly processed into bars or plates and the use for bioabsorbable plates of internal splint in fracture fixation is now under development.
A process for preparing the bioabsorbable polyesters has conventionally been known to carry out polymerization of glycolide or lactide in the presense of a catalyst such as trifluoro antimony or stannous chloride. The process, however, has caused problems due to the toxicity of the catalyst used. Accordingly, preparation processes for eliminating the toxicity problems of the catalyst have been proposed. For example, a process has also been known to use stannous octoate as the catalyst, which compound has been admitted as a nontoxic stabilizer by the Food and Drug Administration in USA [Polymer, Vol. 20, 14-59(1979) ].
Since then various processes have been proposed for the preparation of bioabsorbable polyesters.
For example, the following processes have been proposed for the preparation of glycolic-acid based polymers. (1) Japanese Patent Publication No. 62 - 31736(1987) discloses a preparation process for polyglycolic acid comprising polymerizing glycolide at a temperature of 160.degree. to 180.degree. C. in the presence of stannous octoate in an amount from 0.01 to 0.05% by weight per weight of glycolide and a monohydric alcohol of saturated aliphatic straight chain containing even numbers of from 12 to 18 carbon atoms in an amount from 0.5 to 2.8 times by weight per weight of stannous octoate. (2) Japanese Patent Laid-Open No. 63-17927(1988) discloses a preparation process for polyglycolic acid having an inherent viscosity of 0.85 to 1.1dl/g comprising polymerizing glycolide at a temperature of 220.degree. to 250.degree. C. in the presence of stannous octoate in an amount from 0.001 to 0.005% by weight per weight of glycolide and a monohydric alcohol of aliphatic straight chain containing from 10 to 18 carbon atoms in an amount from 0.11 to 0.22% by mole per mole of glycolide.
On the other hand, processes have also been proposed for the preparation of lactic-acid based polymers. For example, Japanese Patent Laid-Open No. 62-64824(1987) discloses a low molecular weight heterogeneous lactic-acid/glycolic-acid copolymer containing from 25 to 100% by mole of lactic acid structure and from 0 to 75% by mole of glycolic acid structure and having an inherent viscosity of 4 dl/g or less in a 1g/100ml solution of chloroform or dioxane; and a preparation process for the copolymer. An example of the above-mentioned Japanese Patent Laid-Open No. 62-64824(1987) describes a process for conducting polymerization of lactide with glycolide at 160.degree. C. by using 0.2% by weight of stannous octoate as a catalyst in the presence of dl-lactic acid to obtain the desired copolymer.
As described above, various processes have been known in the preparation of bioabsorbable polyesters. When these processes are used for the preparation of bioabsorbable polyesters, it is generally inevitable that from two to several percent of unreacted monomers, i.e., lactide and/or glycolide used as raw materials remains in the resultant polymer. Low molecular weight volatile substances such as impurities having relatively low-boiling points and chain or cyclic oligomers which were formed as by-products during the polymerization have also been known to remain in the resultant polymer.
According to information of the present inventors, glycolic-acid based polymers contain in some cases several percent of residual impurities such as unreacted glycolide and low molecular weight volatile substances. These residual impurities evaporate and generate bubbles in the polymer filament extruded from a nozzle in the spinning step of suture production from the glycolic-acid based polymer. Consequently, end breakage due to the bubbles frequently occurs in the spinning step. It has also been known that the filament obtained is unfavorable because the filament tends to cause fluctuations in strength and hydrolizability
Lactic acid based polymer experience deterioration in storage stability and processability due to the unreacted glycolide and lactide and low molecular weight volatile substances remaining in the polymer. When the polymer is used for a matrix for sustained release of drugs, these impurities tend to make the internal release of drugs intermittent and are liable to cause an early burst phenomenon where a large amount of drugs are released in the initial period. When an internal splint-plate is molded using lactic-acid based polymers of high molecular weight, unreacted monomer and by-products remaining in a large amount lower the strength of the molded splint-plate.
Various problems are thus caused by unreacted monomers and low molecular weight volatile substances remaining in the bioabsorbable polyesters. However, a process for the preparation of bioabsorbable polyesters containing a small amount of these impurities has not yet been proposed.
Glycolic-acid based polymers of high molecular weight which are suitable for spinning are soluble in a few kinds of expensive solvents such as hexafluoroisopropanol(HFIP) and are insoluble in solvents generally used in the industry. Hence, it is industrially unfavorable to apply purification processes such as a reprecipitation method in order to reduce the content of the unreacted monomers and low molecular weight volatile substances. Accordingly, an extraction method can be considered which removes residual monomers by extracting with solvents such as ethyl acetate. The process, however, is also industrially disadvantageous because production steps are complex and problems are further found on removing the extraction solvents remaining in the polymer.
U.S. Pat. No. 3,565,869 discloses a method for removing monomers and low molecular weight volatile substances remaining in the polymer by contacting small pieces of polyglycolic acid with a high temperature inert gas. The present inventors, however, have investigated the process and have found that the process cannot effectively remove the volatile substances such as monomers because the polymer is solid. It takes more than several tens of hours to reduce the amount of residual monomer to the level of 2% or less. The polymer decomposes during the treatment and the molecular weight decreases.
Additionally, the above-mentioned Japanese Patent Laid-Open No.62-64824(1987) discloses a process for the purification of lactic-acid based polymer by reprecipitating the formed polymer after completing the polymerization.
In the process, the formed polymer is dissolved in a good solvent such as chloroform and poured into a poor solvent such as methanol to precipitate the insoluble polymer alone and to remove soluble monomers. The process, however, requires complex steps, lowers the yield of the polymer and is hence industrially unfavorable.
The polymer for use in the matrix for sustained release of drugs in order to continuously release medicine over a long period is desired to be polydisperse in the above-mentioned Japanese Patent Laid-Open No. 62-64824(1987). However, in the purification by the reprecipitation method, the polymer having a relatively low molecular weight is removed by dissolution in the solvent and thus the polymer obtained as insoluble matter has a narrow molecular weight distribution and impaired polydispersibility. Consequently, the polymer is unsuitable for use in the matrix.
The most serious disadvantage of the reprecipitation method is the organic solvent which inevitably remains in the polymer because the organic solvent is used for the purification in the reprecipitation method.
Consequently, the bioabsorbable polyesters purified by the reprecipitation method are difficult to use in medical care.